Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-ß and cognitive function in APP/PS1 mice.

Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aß-induced caspase 1 activation in microglia and this was accompanied by IL-1ß release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aß phagocytosis in vitro, and it reduced Aß accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.

Giant amphipod from the abyssal pacific ocean.

A baited camera has recorded a lysianassid amphipod that is twice as large as the largest amphipod previously recorded. The locality for this mobile omnivore is the sterile bottom of the eastern North Pacific Ocean, at a depth of 5304 meters.

X-linked inheritance in females with chronic granulomatous disease.

Chronic granulomatous disease in males is familial and its transmission is is usually clearly x-linked. The mode of inheritance in females with the syndrome is unknown and the carrier state difficult to identify. Defective polymorphonuclear leukocyte bactericidal activity in this disease is associated with an absence of the respiratory burst generated in stimulated phagocytes and may be detected by the chemiluminescence assay. Polymorphonuclear leukocytes from three of four females with chronic granulomatous disease had extremely low chemiluminescence production, their asymptomatic mothers had intermediate values, and their fathers were normal. Polymorphonuclear neutrophils of two affected males in these kinships generated no chemiluminescence, whereas two of seven female relatives had intermediate values, and all nonaffected males had normal values. In the three families in which leukocytes were studied by nitroblue tetrazolium reduction, two populations of neutrophils were demonstrated for the female patients and/or their mothers. The wide phenotypic variability for clinical disease, evidence of two leukocyte populations in the patients or their mothers, and low but detectable leukocyte chemiluminescence in the affected females is consistent with the Lyon hypothesis of x-chromosome inactivation in these families. The findings suggest an x-linked inheritance in these females with chronic granulomatous disease.

Inhibition of neutrophil lysosome-phagosome fusion associated with influenza virus infection in vitro. Role in depressed bactericidal activity.

The present study examined the effect of various unopsonized strains of influenza A virus on release of myeloperoxidase (MPO) and acid phosphatase in polymorphonuclear leukocytes (PMNL). These results were correlated with the effect that these same viruses had on bactericidal activity in PMNL. Several strains of virus inhibited the fusion of azurophil granules with phagosomes containing Staphylococcus aureus. These same strains inhibited the extracellular release of MPO from PMNL (39-59%) and caused depressed killing (42-77%). In contrast, one of the influenza viruses (X-47a) did not inhibit PMNL MPO release or killing. The data indicate a close relationship between the ability of influenza virus to ablate normal intracellular lysosome-phagosome fusion with subsequent depression of bactericidal functions of PMNL.

The chemiluminescence response of human platelets.

Human platelets and platelet particulate fractions were found to emit a burst of chemiluminescence during incubation with arachidonic acid. The magnitude of light emission was directly related to the number of platelets in the reaction mixture and varied little for the same individual from day to day. The chemiluminescence response of platelets was localized to the particulate fraction and was almost totally oxygen dependent. In addition to arachidonate, seven other polyunsaturated fatty acids, including several that are not prostaglandin precursors, also induced platelet chemiluminescence.A correlation was sought between chemiluminescence and platelet prostaglandin synthesis. Platelets incubated in low concentrations of aspirin, or platelets from subjects who had ingested aspirin, had markedly decreased arachidonic acid-induced chemiluminescence. Salicylic and sulfosalicylic acid had no inhibitory effect. A time-response curve of aspirin inhibition of arachidonate-induced chemiluminescence closely paralleled a time-response curve of aspirin inhibition of malondialdehyde production. Linoleic acid-induced platelet chemiluminescence was also markedly inhibited using aspirin-incubated platelets or platelets from subjects who had ingested aspirin. These studies implicate activation of the enzyme prostaglandin synthetase in the arachidonate-induced platelet chemiluminescence. They provide evidence that linoleic acid may also specifically activate platelet cyclooxygenase to produce electronically excited species capable of light emission.

Mutational analysis of the promoter region of the porA gene of Neisseria meningitidis.

The porA gene encodes the class 1 outer membrane protein (OMP1) in Neisseria meningitidis and is under transcriptional control. Promoter regions of porA from different clinical isolates were sequenced and were found to differ in the number of guanosine residues in a poly(G) track located upstream of the -10 region. Isolates that did not express OMP1 had up to nine G residues in the poly(G) track or an adenosine residue within this poly(G) track. Using beta-galactosidase as a reporter gene, the transcriptional activities of the promoter regions of the porA gene from three strains, two of which do not express OMP1, were assayed in both Escherichia coli and N. meningitidis. Mutations in the poly(G) track were created by site-directed mutagenesis and promoter fusions were further analyzed in E. coli and N. meningitidis. The number of nucleotides in the poly(G) track influenced promoter activity: reduction of a poly(G) track of 12nt by one and by two guanosine residues reduced promoter activity. Within the poly(G) track, replacement of an adenosine residue by a guanosine residue increased the promoter activity; replacement of a guanosine residue by an adenosine residue decreased the activity. The similar transcriptional activities for the mutated promoters in E. coli and N. meningitidis are compatible with similar control mechanisms for transcriptional control in both organisms.

Bactericidal and metabolic function of polymorphonuclear leukocytes.

The bactericidal and metabolic function of the phagocytic system requires integration of several complex humoral and cellular factors responding to different regulators. Polymorphonuclear leukocytes are highly mobile cells, capable of phagocytosis of bacteria or fungi with formation of a "cellular digestive system" containing reactive oxygen radicals, hydrogen ions, and digestive enzymes. The unique metabolism of oxygen in neutrophils results in release of energy as light (chemiluminescence) a response closely associated with microbiol killing. Neonatal neutrophils cope with normal bacterial challenges in vitro as efficiently as adult neutrophils; however, these cells have decreased capacity for locomotion, decreased deformability, decreased phagocytosis in low serum concentrations, and decreased chemiluminescence. These subtle defects in function can be amplified by exaggerated challenge which may be related to a higher incidence of sepsis during the neonatal period.

Should blood cultures be obtained in the evaluation of young febrile children without evident focus of bacterial infection? A decision analysis of diagnostic management strategies.

The technique of decision analysis was used to compare the benefits (prevention of major infectious sequelae of bacteremia) and risks (unnecessary hospitalization and intravenous antibiotic treatment of children whose bacteremia would have resolved spontaneously, discomfort of venipuncture) of alternative diagnostic management strategies in the evaluation of children 3 to 24 months of age with fever (rectal temperature greater than or equal to 39 degrees C) of acute (less than or equal to 4 days) onset and without evident focus of bacterial infection. The diagnostic strategies compared at the initial visit were blood culture in all, blood culture in none, and selective blood culture (restricted to children judged to be at high risk). Probability estimates were based on published epidemiologic studies and case series, and utilities were elicited from mothers of 3- to 24-month-old children and from pediatricians. Based on initial probabilities and utilities, the "no blood culture" strategy had the highest expected utility, followed closely by the "selective blood culture" strategy, with the "blood culture all" strategy a distant third. Sensitivity analyses based on increased risk of major infectious sequelae or of bacteremia had no effect on the ranking of the three initial management options. Eliminating the "disutility" of venipuncture or augmenting the disutility of major infectious sequelae also failed to alter the ranking. Even when an extreme relative disutility for major sequelae was assumed, the "blood culture all" strategy was not favored. Thus, the risk of unnecessary hospitalization and intravenous antibiotic treatment of the relatively large number of children whose bacteremia spontaneously resolves appears to outweigh the benefit of preventing serious infectious sequelae in the few children in whom positive blood culture results permit timely intervention. The explicitness and coherence of the decision analysis approach should help in developing a rational diagnostic approach to the young febrile child.

The chemiluminescence response and bactericidal activity of polymorphonuclear neutrophils from newborns and their mothers.

Chemiluminescence (CL) was measured in the polymorphonuclear neutrophils (PMN) of 18 normal term infants, their mothers, and controls during phagocytosis of opsonized zymosan particles. Chemiluminescence was significantly lower in the PMN of newborns in comparison with the PMN of their mothers and of the controls. Depressed bactericidal activity was demonstrated in newborn PMN, in comparison with the activity of the PMN of their mothers and controls, when challenged with Escherichia coli at large bacteria-PMN ratios. Uptake of radio-labeled bacteria by PMN was identical in newborns, mothers, and controls, which indicates that reduced CL was not a result of impaired ingestion. Therefore, PMN of normal term infants have both depressed oxidative metabolic responsiveness as measured by CL and depressed bactericidal capacity.

The microbiology of serous and mucoid otitis media.

One hundred forty-four serous and mucoid effusions were cultured for aerobic bacteria, Mycoplasma pneumoniae, and virus. Thirty percent of all effusions yielded an unequivocally positive culture for aerobic bacteria. Although serous effusions were culture positive as often as mucoid effusions, Haemophilus influenzae was isolated predominantly from serous effusions and Staphylococcus epidermidis predominantly from mucoid samples. Only one of 73 effusions yielded a viral isolate (Herpesvirus hominis). None of 33 effusions yielded M pneumoniae, and only one of 17 effusions yielded an anaerobe (Propionibacterium). These findings suggest that aerobic bacteria may play a role in the pathogensis of serous and mucoid otitis media.

Parents' versus physicians' values for clinical outcomes in young febrile children.

OBJECTIVE: To compare how parents and physicians value potential clinical outcomes in young children who have a fever but no focus of bacterial infection. METHODS: Cross-sectional study of 100 parents of well children aged 3 to 24 months, 61 parents of febrile children aged 3 to 24 months, and 56 attending staff physicians working in a children's hospital emergency department. A pretested visual analog scale was used to assess values on a 0-to-1 scale (where 0 is the value of the worst possible outcome, and 1 is the value for the best) for 22 scenarios, grouped in three categories according to severity. Based on the three or four common attributes comprising the scenarios in a given group, each respondent's value function was estimated statistically based on multiattribute utility theory. RESULTS: For outcomes in group 1 (rapidly resolving viral infection with one or more diagnostic tests), no significant group differences were observed. For outcomes in groups 2 (acute infections without long-term sequelae) and 3 (long-term sequelae of urinary tract infection or bacterial meningitis), parents of well children and parents of febrile children had values that were similar to each other but significantly lower than physicians' values for pneumonia with delayed diagnosis, false-positive diagnosis of urinary tract infection, viral meningitis, and unilateral hearing loss. For bacterial meningitis with or without delay, however, the reverse pattern was observed; physicians' values were lower than parents'. In arriving at their judgment for group 2 and 3 scenarios, parents gave significantly greater weight to attributes involving the pain and discomfort of diagnostic tests and to diagnostic error, whereas physicians gave significantly greater weight to attributes involving both short- and long-term morbidity and long-term worry and inconvenience. Parents were significantly more likely to be risk-seeking in the way they weighted the attributes comprising group 2 and 3 scenarios than physicians, ie, they were more willing to risk rare but severe morbidity to avoid the short-term adverse effects of testing. CONCLUSIONS: Parents and physicians show fundamental value differences concerning diagnostic testing, diagnostic error, and short- and long-term morbidity; these differences have important implications for diagnostic decision making in the young febrile child.

Role of the complete blood count in detecting occult focal bacterial infection in the young febrile child.

Previous studies of the value of the complete blood count (CBC) in distinguishing viral from bacterial infection in young febrile children have failed to exclude children with clinically evident bacterial infection and thus have inflated the positive predictive value of the test for occult focal infection. We prospectively studied 2492 children 3-24 months of age who presented to a children's hospital emergency department between March 1989 and August 1990 with fever (> or = 38.0 degrees C) of acute (< or = 4 days) onset but no evident bacterial focus of infection, 433 (17.4%) of whom received a CBC. We also carried out an 8-year retrospective analysis to estimate prior, or pre-test, probabilities (prevalences) and examine CBC results for rare occult bacterial infections (meningitis, osteomyelitis, and septic arthritis). Estimated prior probabilities for the four most common categories of infection that can be diagnosed at the initial visit were: non-pneumonitic viral infection, 88.6% in boys and 86.0% in girls; pneumonia, 8.5% in both sexes; urinary tract infection (UTI), 3.0% in boys and 5.5% in girls; and bacterial meningitis, 0.0066% in both sexes. The likelihood (sensitivity) of a total white blood cell (WBC) count > or = 15,000/mm3 was 25.5, 64.5, 62.5, and 50.0% for viral infection, pneumonia, UTI, and meningitis, respectively. Among children with a high total white blood cell count, neither a total polymorphonuclear count > or = 10,000/mm3 nor a band count > or = 500/mm3 was associated with significantly elevated likelihoods for occult pneumonia or UTI, a finding confirmed by multiple logistic regression analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-phase neurologic complications of Haemophilus influenzae type b meningitis: association with developmental problems at school age.

The purposes of this study were to describe the incidence of acute-phase neurologic complications in a sample of 126 children with Haemophilus influenzae type b meningitis, and to determine if these complications were associated with higher rates of learning and behavior problems at school age. Risks were assessed by comparing rates of adverse psychoeducational outcomes in the 53 children in the sample with complications to corresponding outcome rates in the 67 children who were free of neurologic complications and who did not have abnormal electroencephalograms (EEGs) or computed tomographic (CT) scans. Comparisons were made by means of logistic regression analysis. Twenty-nine children (23% of the sample) had seizures, 16 (13%) were comatose or obtunded, 15 (12%) had sensorineural hearing loss, 8 (6%) had hemiparesis, and 7 (6%) had cranial nerve deficits other than hearing loss. Relative to children without complications, those with complications had higher rates of grade repetition and substandard performance on neuropsychological and achievement testing. Adverse outcomes, however, consisted primarily of more subtle cognitive and learning problems; only two of the children in the sample obtained prorated IQ scores below 70. Sequelae were associated with persistent neurologic deficits and bilateral hearing loss, as well as with transient symptoms including seizures, coma, and hemiparesis. While study findings argue against adverse consequences for the vast majority of children treated for this disease, the results clarify learning and behavior outcomes and indicate which children are at greatest risk.

Mercury content of small pan fish from New York State waters.

Yellow perch (Perca flavescens) and pumpkin seed (Lepomis gibbosus) were sampled from 16 waters in New York-State and analyzed for total mercury concentration. The levels of mercury in the fish were all well below the safe guideline for human consumption (1 ppm of mercury, fresh weight) of the U.S. Food and Drug Administration. Factors affecting the mobility, methylation and absorption of mercury by fish are discussed.

Toxic and nutrient element concentrations in soft tissues of zebra and quagga mussels from Lakes Erie and Ontario.

Zebra and quagga mussels were collected from Lakes Erie and Ontario in 1997 and the soft mussel tissues were analyzed for Ca, Cd, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, Pb, Se, Sr, V and Zn. No consistent relationships were apparent when comparing element concentrations in soft mussel tissues and mussel type, size range or sampling location. Literature dealing with the absorption of metals by both mussel types is reviewed.

Biochemical and immunochemical characteristics of middle ear effusions in relation to bacteriological findings.

Experimental otitis media was produced in chinchillas by eustachian tube obstruction or pneumococcal infection. Sequential changes in the histology of the middle ear mucosa and enzyme profile of the middle ear effusions (MEE) were studied. In serous otitis media (SOM) which followed tubal obstruction, the subepithelial space was widened by edema and capillary dilatation, and the middle ear space was filled with serous fluid. Slight hyperplasia of epithelial cells was also observed. The subepithelial space remained widened with mild fibrous change and capillary dilatation, and slight hyperplasia of epithelial cells persisted 42 days after obstruction. In purulent otitis media (POM), which followed inoculation of pneumococci into the middle ears, metaplasia of the epithelial layer from flat to columnar cells was observed. The subepithelial space was widened with loose fibrous connective tissue proliferation, vascular dilatation and inflammatory cell infiltration. Both lactate dehydrogenase (LDH) and lysozyme levels in MEE were higher in the POM group than in the SOM group. When bacterial enzymes, hyaluronidase and lipase activity were measured in MEE and plotted together with the percentage of positive culture of the MEE at different times after the experimental infection, the enzyme activities decreased with the clearing of bacteria and along with the resorption of inflammatory changes of middle ear mucosa evidenced by histology. In human MEE studies, immunoglobulins (IgG, IgA, IgM) of MEE were higher than in serum except IgM in serous MEE. The IgG content of MEE in the culture-negative group was higher than in the culture-positive group. Possible mechanisms for this difference were discussed.

Epiglottitis in Canada: A multiregional review.

Epiglottitis is an acute, life threatening infection usually caused by Haemophilus influenzae type b. Although antibiotic therapy is an important part of management, the optimal route and duration is unknown. A multicentre retrospective review of 305 children with epiglottitis was carried out in order to relate antibiotic therapy to hospital course and outcome, as well as to examine regional variation in patient demographics, clinical presentation and course of disease. A standardized form was used to extract data from hospital records. Although management varied significantly among the six centres in terms of mean duration of intubation (46 to 81 h), intravenous antibiotic therapy (3.8 to 5.7 days) and hospital stay (5.3 to 8.4 days), there were no significant centre-related differences in epidemiology, clinical course or outcome of epiglottitis. An extraepiglottic focus of infection was present in 15% of patients and included three with septic arthritis and one with meningitis. The duration of fever in hospital and maximum recorded temperature in hospital were significantly greater for children with extraepiglottic infection compared to those with epiglottitis alone. The data presented in this review suggest that most children with epiglottitis have an uncomplicated course and respond rapidly to antimicrobial therapy following airway securement. A short period of intravenous and oral antibiotic therapy is likely adequate for most children with epiglottitis. A well designed multicentre prospective trial is still needed to determine the optimal duration of antibiotic therapy.